essential thrombocythemia
The order in which genetic mutations are acquired determines how myeloproliferative neoplasms (MPNs) behave, according to research published in NEJM.
Investigators found that mutation order impacts everything from the type of MPN a patient develops to how the disease responds to treatment.
“This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them,” said study author David Kent, PhD, of the University of Cambridge in the UK.
“For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.”
To uncover this finding, Dr Kent and his colleagues screened 246 MPN patients for mutations in JAK2 and TET2. By studying patients who carried both mutations, the team was able to determine which mutation came first and study the effect of mutation order on the behavior of hematopoietic stem cells.
The investigators found that patients who acquired mutations in JAK2 prior to those in TET2 displayed aberrant blood counts more than a decade earlier.
These patients were more likely to present with polycythemia vera than with essential thrombocythemia, and they were more likely to develop thromboses.
At the same time, JAK2-mutant progenitors from these patients exhibited increased sensitivity to the JAK1/2 inhibitor ruxolitinib in vitro.
“This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy,” said study author Tony Green, MD, PhD, of the University of Cambridge.
“These results show how the study of MPNs provides unparalleled access to the earliest stages of tumor development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer.”
